Methylamine → 1-(4-(2,5-Difluoro-4-(1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-yl)-3-methylurea

HRID 1050874Notes

Reaction equation

HRID 1050874 reaction equation
C(O[C:4]1[CH:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6](=[O:17])[C:5]=1[C:18]([NH:20][C:21]1[C:40]([F:41])=[CH:39][C:24]([O:25][C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33](=O)[O:34]C(C)=C)[CH:27]=2)=[C:23]([F:42])[CH:22]=1)=[O:19])C.[CH3:43][NH2:44].C[N:46]1[CH2:50]CCC1>>[F:42][C:23]1[CH:22]=[C:21]([NH:20][C:18]([C:5]2[C:6](=[O:17])[N:7]([C:10]3[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=3)[CH:8]=[CH:9][C:4]=2[NH:46][CH3:50])=[O:19])[C:40]([F:41])=[CH:39][C:24]=1[O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:33]([NH:44][CH3:43])=[O:34])[CH:27]=1

Participants

4

Reactant 3

HCID 6329MethylamineHCID 84541-MethylpyrrolidineHCID 86703365Prop-1-en-2-yl (4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2,5-difluorophenoxy)pyridin-2-yl)carbamate

Product 1

HCID 715758751-(4-(2,5-Difluoro-4-(1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-yl)-3-methylureaYield 18%

Procedure

Prop-1-en-2-yl (4-(4-(4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamido)-2,5-difluorophenoxy)pyridin-2-yl)carbamate (0.14 g, 0.24 mmol) was treated with a solution of N-methylamine (2.0 M in THF, 4 mL, 8 mmol) and N-methylpyrrolidine (0.021 g, 0.24 mmol), and was stirred at RT for 3 h. The solid was collected by filtration and further purified by silica gel chromatography (EtOAc). The purified residue was treated with MeCN/H2O (1:1, 4 mL), frozen and lyophilized to obtain 1-(4-(2,5-difluoro-4-(1-(4-fluorophenyl)-4-(methylamino)-2-oxo-1,2-dihydropyridine-3-carboxamido)phenoxy)pyridin-2-yl)-3-methylurea (23 mg, 18% yield) as an off-white powder. 1H NMR (400 MHz, DMSO-d6): δ 13.21 (s, 1 H), 10.35 (d, J=6.0 Hz, 1 H), 9.13 (s, 1 H), 8.48 (dd, J=12.9, 7.2 Hz, 1 H), 8.06 (d, J=5.9 Hz, 1 H), 7.83 (s, 1 H), 7.72 (d, J=7.8 Hz, 1 H), 7.48 (m, 3 H), 7.34 (t, J=8.5 Hz, 2 H), 6.92 (s, 1 H), 6.57 (dd, J=6.0, 2.4 Hz, 1 H), 6.24 (d, J=7.9 Hz, 1 H), 3.01 (d, J=5.0 Hz, 3 H), 2.66 (d, J=4.6 Hz, 3 H); MS (ESI) m/z: 539.2 (M+H+).

Workup

  1. filtrationThe solid was collected by filtration
  2. customfurther purified by silica gel chromatography (EtOAc)
  3. additionThe purified residue was treated with MeCN/H2O (1:1, 4 mL)
  4. temperaturefrozen

Sources & evidence

ORD record
ord-dacd03a858aa4b43900a37f167c256d8
Source dataset
uspto-grants-2016_07
Patent number
US09387202B2

Reaction notes

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